Increases in pulmonary related incidents of morbidity and mortality have been epidemiologically associated with exposure to particulate matter (PM). Due to its heterogeneity and complex physicochemistry, the underlying mechanism(s) of PM toxicity are poorly understood. This proposal examines the hypothesis that physicochemical components of PM initiate inflammation by activation of irritant (i.e., capsaicin, acid-sensitive) receptors located on sensory nerve endings and airway epithelial target cells. This activation results in an influx of extracellular calcium and release of neuropeptides and inflammatory cytokines, which proceed to initiate and sustain events of airway inflammation ands hypersensitivity. The response of irritant receptors to PM will be examined in primary cultures of sensory dorsal root ganglion neurons and in human bronchial epiothelial cells. Biophysical (e.g., patch clamp, calcium imaging) and immunological (e.g., cytokine release) endpoints will be used to characterize the response to various urban, industrial and ambient PM. The physicochemical properties of selected PM and their separate soluble and particulate fractions will be determined and examined for their cellular effects. Based on these data, synthetic particle analogues will be designed, that resemble PM particles in size and surface charge, to assess the inflammatory contribution of specific PM components. Physiological and pharmacological evaluation of the responses to PM will identify and characterize the contribution of culpable irritant receptors to the PM-mediated effects. In addition, the involvement of other cellular pathways (i.e., calcium channels, acid-sensitive exchangers) will be examined. The mechanistic approach outlined in this proposal will identify the responsible factors and target sites contributing to PM toxicity.